TETRAHYDROBIOPTERIN ALTERS SUPEROXIDE AND NITRIC-OXIDE RELEASE IN PREHYPERTENSIVE RATS

Constitutive nitric oxide synthase (cNOS) with insufficient cofactor ( 6R)-5,6,7,8-tetrahydrobiopterin (H4B) may generate damaging superoxide (O-2(-)), This study was designed to determine whether cNOS-dependent generation of O-2(-) occurs in spontaneously hypertensive rats (SHR) before the onset of hypertension, Aortas from 4-wk-old SHR and Wistar- Kyoto rats were used. cNOS was stimulated by calcium ionophore A23187, In situ measurements of nitric oxide and hydrogen peroxide by electro chemical sensors and O-2(-) production by chemiluminescence method wer e performed, Isometric tension was continuously recorded, H4B by high performance liquid chromatography and [H-3]citrulline assay were deter mined in homogenized tissue, The A23187-stimulated production of O-2(- ) and its superoxide dismutase product hydrogen peroxide were signific antly higher, whereas nitric oxide release was reduced in SHR aortas, with opposite results in the presence of exogenous H4B. Furthermore, N -G-monomethyl-L-arginine inhibited the generation of cNOS-dependent O- 2(-) by similar to 70%. Natural H4B levels were similar in both strain s; however, equivalent. cNOS activity required additional H4B in SHR. The endothelium-dependent relaxations to A23187 were significantly inh ibited by catalase, and enhanced by superoxide dismutase, only in SHR; however, these enzymes had no effect in the presence of H4B. Thus, dy sfunctional cNOS may be a source of O-2(-) in prehypertensive SHR and contribute to the development of hypertension and its vascular complic ations.